4,5-epoxy-1,3,4,5-tetrahydro-2h-1,4-benzodiazepin-2-ones

ABSTRACT

4,5-EPOXY - 1,3,4,5 - TETRAHYDRO-2H-1,4-BENZODIAZEPIN2-ONES ARE PREPARED BY LIGHT IRRADIATION OF A CORRESPONDINGLY SUBSTITUTED 1,3-DIHYDRO-2H-1,4-BENZODIAZEPIN-2-ONE 4-OXIDE. THE EPOXY COMPOUNDS ARE USEFUL AS SEDATIVES, MUSCLE RELAXANTS AND ANTICONVULSANT AGENTS. THESE COMPOUNDS HAVE ALSO EXHIBITED ANTIBACTERIAL ACTIVITY AGAINST CERTAIN SPECFIC ORGANISMS.

United States Patent 3,591,581 4,5-EPOXY-1,3,4,5-TETRAHYDRO-2H-l,4- BENZODIAZEPIN-Z-ONES George Francis Field, West Caldwell, Robert Ye-Fong Ning, Verona, and Leo Henryk Sternbach, Upper Montclair, N.J., assignors to Holfmann-La Roche llnc.,

Nutley, NJ.

No Drawing. Continuation-impart of application Ser. No. 766,649, Oct. 10, 1968. This application June 23, 1969, Ser. No. 835,720

Int. Cl. C07d 53/06 U.S. Cl. 260239.3 24 Claims ABSTRACT OF THE DISCLOSURE 4,5-epoxy 1,3,4,5 tetrahydro-ZH-1,4-benzodiazepin- 2-ones are prepared by light irradiation of a correspondingly substituted 1,3-dihydro-2H-l,4-benzodiazepin-2-one 4-oxide. The epoxy compounds are useful as sedatives, muscle relaxants and anticonvulsant agents. These compounds have also exhibited antibacterial activity against certain specific organisms.

RELATED APPLICATIONS This case is a continuation-in-part of co-pending US. application Ser. No. 766,649, filed Oct. 10, 1968, now abandoned.

DESCRIPTION OF THE INVENTION The present invention relates to pharmacologically useful compounds of the following formula wherein R and R independently each are hydrogen, halogen, trifluoromethyl, amino, lower alkylamino, nitro, lower alkyl, lower alkylthio, lower alkylsulfonyl and lower alkyl-sulfinyl; R is hydrogen, lower alkyl, cycloalkyl, aryl alkyl and lower alkenyl and R is hydrogen, halogen, trifluoromethyl and lower alkyl.

As used herein, the term lower alkyl comprehends straight or branched chain hydrocarbon groups having from 1-7 carbon atoms, preferably 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl or the like. The term lower alkenyl refers to both straight and branched chain unsaturated hydrocarbon groups such as allyl and the like. The term cycloalkyl comprehends a cyclic hydrocarbon group having from 3-6 carbon atoms in the ring, such as cyclopropyl, cyclobutyl, cyclopentyl and the like. Halogen represents all four halogens, i.e., fluorine, iodine, chlorine and bromine, With fluorine, chlorine and bromine the halogens of preference in the present invention. The term arylalkyl comprehends phenyl-lower alkyl groups such as benzyl.

In a preferred embodiment of the present invention, one member of R and R represents a halogen group substituted at the 7-position of the benzodiazepine ring and the other is hydrogen. In a most preferred embodiment the halogen substituent is a chloro group. In such preferred embodiment, R is hydrogen or lower alkyl, most preferably hydrogen or methyl. The meaning of R in such preferred embodiment is hydrogen or halogen. When R is halogen, it most preferably is substituted at the 2 or ortho position and in a most preferred embodiment is fluorine.

Compounds of Formula I are most conveniently prepared by irradiating a compound of the following formula where R, R R and R are as above.

The reaction described above proceeds by irradiation with light energy of a specific range of wavelengths which is obtained from a mercury arc lamp. A most preferred light source for the purpose of the irradiation used in the preparation of compounds of the present invention consists of a medium pressure mercury arc lamp which is fitted with a Pyrex filter sleeve to remove light of wavelengths less than about 300 mg. The resulting light beam Will contain Wavelengths substantially in the range between about 300 to about 400 m which light will be of sufiicient energy to effect the desired irradiation reaction but will be below the energy levels which cause degradation of the compounds of Formula I.

The irradiation reaction is most conveniently conducted in an inert organic solvent conventionally employed in irradiation procedures. Suitable solvents include, for example, ethers such as tetrahydrofuran, esters, ketones, hydrocarbons and halogenated hydrocarbons. Tetrahydrofuran is a solvent of preference.

The subject reaction is conducted under an inert atmosphere such as for example a nitrogen, argon, helium, etc. atmosphere. The reaction temperature employed is not critical to this process and conventional temperatures useful in irradiation procedures can be used, such as for example, a temperature in the range of from about to (3., most preferably in the range of from about 10 to 30 C.

Examples of compounds which correspond to Formula I and which are thus representative of the present invention include the following:

7-chloro-4,5-epoxy-S-phenyl-l,3,4,5-tetrahydr0-2H-1,4-

benzodiazepin-Z-one 7-chloro-4,5-epoxy-l-methyl-S-phenyl-1,3,4,5-tetrahydro- 2H-1,4-benZodiazepin-2-one 4,5-epoxy 5 phenyl 1,3,4,5 tetrahydro 2H 1,4-

benzodiazepin-Z-one.

7 chloro 5 (2 chlorophenyl) 4,5-epoXy-1-methyll,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one.

l benzyl 7 chloro 4,5 epoxy 5 phenyl 1,3,4,5

tetrahydro-ZH-1,4-denzodiazepin-2-one.

7, 8 dimethyl 4,5 epoxy 5 phenyl 1,3,4,5-tetrahydro- 2H-1,4-benzodiazepin-2-one.

4,5 epoxy 5 phenyl 1,3,4,5 tetrahydro-7-trifiuoromethyl-2H-1,4-benzodiazepin-2-one.

7 chloro 4,5 epoxy 5 (Z-fluorophenyl)-1,3,4,5-

tetrahydro-ZH-1,4-benzodiazepin-2-one.

7 chloro 5 (2-chlorophenyl)-4,5-epoxy l,3,4,5-terahydro-2H-1,4-benzodiazepin-2-one.

4,5 expoy 5 (2 fluorophenyl) l,3,4,5 tetrahydro- 7-methylthio-2H-l,4-benzodiaZepin-2-one.

4,5 epoxy 7 methylsulfonyl 5 phenyl 1,3,4,5 tetrahydro-2H-1,4-benzodiazepin-2-one.

4,5 epoxy 5 phenyl 1,3,4,5 tetrahydro 7 methylthio-2H-1,4-benzodiazepin-2-one.

The compounds of Formula I are useful as pharmaceuticals and are characterized by activity as sedatives, muscle relaxants, and anti-convulsant agents. These compounds can be used in the form of conventional pharmaceutical preparations; for example, the aforesaid compounds can be mixed with conventional organic or inorganic, inert pharmaceutical carriers suitable for parenteral or enteral administration such as, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oil,

wherein the compound had an ED of 480 mg./kg. p.o. and 800 mg./ kg. p.o., respectively. The Anti-metrazol test wherein and ED of 32.7 mg./kg. p.o. was observed demonstrates in another mode the sedative and/ or anticonvulsant activity of the subject compound.

The following examples are illustrative, but not limitative of this invention. All temperatures are in degrees Centigrade.

EXAMPLE 1 gums, or the like. They can be administered in conven- 10 tional pharmaceutical forms, e.g., solid forms, for ex- Pfeparatlon f 7 Chlofo P y -P y 5- ample, tablets, dragees, capsules, suppositories or the like; ititfahYdm-ZH-1,4-bBI1Z0d1aZeP1n-2-m1e or in liquid forms, for example suspensions, or emul- A Solution of 263 g (0.0935 mole) of 7 ch10r0 13, P Moreover the f f i composltl'fms dihydr0-5-phenyl-2H-1,4-benz0diazepin-2-0ne 4-oxide in talmng Fompounds of i mventlo, can be Sublecteg to 1.4 liters of tetrahydrofuran was irradiated with a Hanconventional pharmaceutical exped1ents such as sterrhza- Ovia 250 W medium pressure mercury arc (N0. 654 A) P and can contam nvent1,n a1 pharmaceutlcal F Q through a Pyrex filter, under nitrogen atmosphere at lents Such as preservatlvth stablhzmg t emulslfymg for 22 hours. The solution was concentrated in vacuo to agents salts for thefidlustment of osmojuc pressure or a small volume. Addition of hexane and chilling gave the The Fomposltlcgns can also contam other them' 20 above-titled product as colorless prisms, melting with Y if i 1 d sudden decomposition in the temperature range of 136- f e p g Osfage .3 can a 150. An analytical sample was prepared by recrystallizrom a out 1 i 0 0 e a comPoun S 0 ations from tetrahydrofuran methanol mixtures, M.P. Formula I. Suitable oral dosage regimens in warm- 0 D blooded mammals comprise from about 1 mg./kg. per 25 day to about 500 mg./kg. per day. Suitable parenteral EXAMPLE 2 dosage regimens in warm-blooded mammals comprise Preparation of 7-chloro-4,5-epoxy-l-methyl-S-phenylfrom about 1 mg./kg. per day to about 500 mg./kg. per 1,3,4,5-tetrahydro-2H-1,4-benZodiazepin-2-one Howfiver for any paiflcular i s.p.eclfic Asolution of g. (0.10 mole) of 7-chloro-1,3-dihydrodosage regimen should be ad usted according to individual 30 1 methy1 5 phpny1 2H 1 4 benzodiazepin z one 4 oxide in F and the prOfe.S.SlOnal l i of t person admm' 1.4 liters of tetrahydrofuran was irradiated under the F or g i p g g g g afore' same conditions as described in Example 1. The irradiated :2; g ifigzijg g i g g i 23 2 55 solution was evaporated to dryness.- Trituration of the h p f residual gum with a small amount of ethanol caused to any extent mutt 6 Scope or Practlce O t is mven crystallization of the above-titled product which was re- Th muscle relaxant? Sedatwe and antl-convulszint crystallized once from ethanol to yield colorless prisms, activity of a representative compound of the present 1n- MP vention, i.e., 7 -chloro-4,5-epoxy-5-phenyl-1,3,4,5-tetra- EXAMPLE 3 hydro-2H-1,4-benzodiazepin-2-one was determined by using a series of biological screening tests. In the Foot 40 In a similar manner to the procedure described 111 Shock test (measuring the anti-anxiety and/or muscle Example 1, the following compounds of the Formula I relaxant activity) the subject compound had a were prepared.

TABLE I Recrystal- M.P., C. lization Yield Time Name of compound (dec.) solvent 1 (percent) THF solution irradiated 3 (hrs.)

(a) 4,5-epoxy-5-phenyl-1,3,4,5tetrahydro-2H-1,4-benzodiazepin-2-onc 159 A 96 2.0 g. in 1.41 1.5 (b) 7-chloro-5-(2-ch1orophenyl)-4,5-epoxy-1-mct11y1-1,3,4,5tetrahydro-2H- 119-121 A 61 0.50 g. in 1.5

1,4-benzodiazepin-2-ono. (c) 1-benzy1-7-ch1oro-4,5-epoxy-5-phenyl-1,3,4,5tetrahydro-2H'1,4 148-150 C 63 .....do 1.5

benzodiazcpin-2-ono. (d21 7,s-dimethyl-4,5 eopxy-5-phcnyl-1,3,4,5tetrahydro-2H-1,4rbeuzo- 163 O 87 .d0 0. 5

' e 20 (e) ii dgp r ixyphenyl-l,3,4,5-tetrahydrtH-triiluoromethy1-2H-1,4- 128-131 C 80 1.0 g. in 150ml 0.5

benzodiazepin-Z-one. (i)7-chloro-4,5-epoxy-5-(2-fiuorophenyl)-1,3,4,5-tetrahydro-2H-1,4- 139 C 80 20 g. in 1.41 19 benzodiazepin-2-one. (g?) 7-choro-5-(2-ghlorophcnyl)-4,5-epoxy-1,3,4,5tetrahydro-2H-L4- 127 C 55 d0 30 11 G l -O (11) 2, poiria-flu iophenyl)-,3-4,5-tetrahydro7-mcthy1thio-2H-1,4. 126 A 06 0.50 g. in 150ml 0.25

benzodiazcpin-2-one. (i)b4,5 c8pxy-7imethylsulfonyl-5-phcny1-1,3,4,5-tctrahydro-2H-1,4- 165 A 88 0.60 g. in 1.41 0.75

cnzo c n-2-0 c. (j) 4,5-cpo g -pheng hhi4,5-tetrahydro-7-methylthio2H-1,4-benzo- 128 A 82 0.50 g. in 150 m1 0.25

diazcpin-2-one.

1 Characterized by sudden decompositions; sometimes variable with the rate of heating.

2 A-THF-hexanc; B-EtOH; O=CgHs n-heptanc.

3 Irradiation performed under an atmosphere of nitrogen gas, with a 250 W. Hanovia mercury lamp #05411, filtered through a Pyrex sleeve inside a quartz immersion well, cooled by running tap water.

4 The starting material for this experiment may be prepared as follows: A solution of 11.28 g. (40 mmoles) oi 1,3-diliydro-7-methylthio4phcnyl- 211-1,4-1)euzodiazepiu-Q-one and 32.6 g. mmolcs) oi m-chloroperbenzoic acid in 800 ml. 011201? was allowed to stand at room temperatur c After 18 hours, the precipitated solids were collected and combined with two more crops of solids obtained from concentration of the CHzCiz solution. The solids were suspended in excess aqueous NaHCO; and H20 followed by drying weighed 6.0 g. After two rcerystallizations from DMF-EtOH: 5.14 g. of 1,B-dihydro-7-methylsuh'ony1-4-pheny1-2H-1,4- bcnzodiazcpin-2-one 4-oxide was obtained in a colorless amorphous form, M.P. 256-257 (dec.).

EXAMPLE 4 Per 1.3 gm. Suppository formulation: Suppository, gm.

7-chloro 4,5 epoxy 5 phenyl-l,3,4,5- tetrahydro-2H-1,4-benzodiazepin-2-one 0.010 Wecobee M 1.245

Carnauba wax 0.045

E. F. Drew Company, 522 Fifth Ave., New York, N. Y.

Procedure 1) The Wecobee M and the carnauba wax were melted in a suitable size glass-lined container (stainless steel may also be used), mixed well and cooled to 45 C.

(2) 7-chloro 4,5 epoxy 5 phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin 2 one which had been reduced to a fine powder with no lumps, was added and stirred until completely and uniformly dispersed.

(3) The mixture was poured into suppository molds to yield suppositories having an individual weight of 1.3 grams.

(4) The suppositories were cooled and removed from molds. They were then individually wrapped in wax paper for packaging (foil may also be used).

EXAMPLE 5 Capsule formulation: Per capsule, mg. 7-chloro 4,5 epoxy 5 phenyl-l,3,4,5-tetrahydro-ZH-1,4-benzodiazepin-2-one Lactose, U.S.P 165 Corn starch, U.S.P. 30 Talc, U.S.P. 5

Total weight 210 Procedure EXAMPLE 6 Tablet formulation: Per tablet, mg.

7-chloro 4,5 epoxy-5-phenyl-1,3,4,5-tetrahydro-2I-I-1,4-benzodiazepin-2-one 25.00 Dicalcium phosphate dihydrate, unmilled 175.00

Corn starch 24.00 Magnesium stearate 1.00

Total weight 225.00

Procedure (1) 7-chloro 4,5 epoxy 5 phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin 2 one and corn starch were mixed together and passed through a No. 00 screen in Model J Fitzmill with hammers forward.

(2) This premix was then mixed with dicalcium phosphate and one-half of the magnesium stearate, passed through a No. 1A screen in Model I Fitzmill with knives forward, and slugged.

(3) The slugs were passed through a No. 2A plate in a Model D Fitzmill at slow speed with knives forward, and the remaining magnesium stearate was added.

(4) The mixture was mixed and compressed.

What is claimed is:

1. A compound of the formula wherein R and R independently each are hydrogen, halogen, trifluoromethyl, amino, lower alkylamino, nitro, lower alkyl, lower alkylthio, lower alkylsulfonyl and lower alkylsulfinyl; R is hydrogen, lower alkyl, cycloalkyl containing from 3-6 carbon atoms, phenyl-lower alkyl and lower alkenyl and R is hydrogen, halogen, trifluoromethly, and lower alkyl.

2. A compound of claim 1 wherein R is hydrogen and R is halogen substituted at the 7-position of the benzodiazepine ring.

3. A compound of claim 2 wherein R is chlorine and R is lower alkyl.

4. A compound of claim 3 wherein R is methyl.

5. A compound of claim 3 wherein R is hydrogen.

6. A compound of claim 3 wherein R is chlorine and R is hydrogen.

7. The compound of claim 6 which is 7-chloro-4,5- epoxy-S-phenyLl,3,4,5-tetrahydro-2H-l,4 benzodiazepin- 2-one.

8. The compound of claim 4 which is 7-chloro-4,5- epoxy-l-methyl 5 phenyl 1,3,4,5 tetrahydro-2H-1,4- benzodiazepin-Z-one.

9. The compound of claim 1 which is 4,5-epoxy-5- phenyl-l,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one.

10. The compounds of claim 1 wherein R is halogen.

11. A compound of claim 10 which is 7-chloro-5-(2- chlorophenyl)-4,5-epoxy-l-methyl 1,3,4,5 tetrahydro- 2H-1,4-benzodiazepin-2-one.

12. The compound of claim 10 which is 7-chloro-4,5- epoxy-5-(2-fluorophenyl) 1,3,4,5 tetrahydro 2H-1,4- benzodiazepin-Z-one.

13. The compound of claim 10 which is 7-ch1oro-5-(2- chlorophenyl)-4,5-epoxy-1,3,4,5 tetrahydro 2H 1,4- benzodiazepin-2-one.

14. The compound of claim 10 which is 4,5-epoxy-5- (2-fluorophenyl)l,3,4,5-tetrahydro 7 methylthio 2H- 1,4-benzodiazepin-2-one.

15. A compound of claim 1 wherein R is phenyl-lower alkyl.

16. The compound of claim 15 which is 1-benzyl-7- chloro-4,5-epoxy 5 phenyl 1,3,4,5-tetrahydro-2H-1,4- benzodiazepin-Z-one.

17. A compound of claim 1 wherein R and R are both lower alkyl.

18. The compound of claim 17 which is 7,8-dimethyl- 4,5-epoxy-5-phenyl 1,3,4,5 tetrahydro 2H-1,4-'benzodiazepin-Z-one.

19. The compound of claim 1 which is 4,5-epoxy-5- phenyl-1,3,4,5-tetrahydro 7 trifluoromethyl 2H 1,4- benzodiazepin-Z-one.

20. The compound of claim 1 which is 4,5-epoxy-5- phenyl-1,3,4,5-tetrahydro 7 methylthio 2H 1,4- benzodiazepin-Z-one.

21. A process for the preparation of compound of the formula wherein R and R are each independently hydrogen, halogen, trifiuoromethyl, amino, lower alkylamino, nitro, lower alkyl, lower alkylthio, lower alkylsulfonyl and lower alkylsulfinyl; R is hydrogen, lower alkyl, cycloalkyl containing from 3-6 carbon atoms, phenyl-lower alkyl and lower alkenyl; and R is hydrogen, halogen, trifluoro- 7 8 methyl and lower alkyl which process comprises irradiat- 23. The process of claim 22 wherein said desired light ing a compound of the formula energy range is obtained by filtering the light through a R2 Pyrex filter. GJ 24. A compound of claim 1 which is 4,5-epoxy-7- 5 methyl-sulfonyl-S-phenyl 1,3,4,5 tetrahydro 2H 1,4- benzodiazepin-Z-one.

N4 References Cited 0 Sternbach et al., J. Org. Chem. vol. 27, pp. 4671-2 H-ENRY R. JILES, Primary Examiner R. T. BOND, Assistant Examiner. wherein R, R R and R are as above with llght energy having a major portion of its energy in the range between 15 US. Cl. X.R. about 300 to 400 m 22. The process of claim 21 wherein said light energy 204158 260 239'3 424-244 is derived from a medium pressure mercury arc lamp.

53 5 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,59 ,5 Dat d July 6, 1971 Inventor) Field, Ning and Sternbach It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

r- Column 2 lines 6-15 in formula II 2 i N I should be UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 59 5 Dated Inventor(s) Field Ning and ternbach It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 6 line 25 claim 10 The compound" should be A compound Column 6, line 26 claim 11 "A compound" should be Zhe compound Column 6 line 54 claim 21 "A process for the preparation of compound should be A process for the preparation of a compound UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,591,581 Dated Inventm-( Field, ng and Sternbach It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 7, lines 4-15 in claim 21 should be l Signed and sealed this 9th day of May 1972 (SEAL) Attest:

EDWARD M. FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents 

